Chronic allograft nephropathy (CAN) remains the most common cause of graft loss. However, the term CAN does not delineate the specific underlying pathologic process but rather refers to the chronic injury resulting from multiple potential factors. More recently it has been suggested that the pathologic findings of chronic allograft glomerulopathy, chronic allograft arteriopathy, and lamination of the peritubular capillary basement membrane, arise due to a chronic immunologic process and therefore should be referred to as true chronic rejection. There are extensive animal and initial human studies suggesting that indirect recognition of alloantigen and/or alloantibody responses mediate this process. There are however no studies which prospectively examine whether the development of the chronic allograft rejection correlates with immune reactivity. The principal hypothesis of this project is that chronic rejection is mediated by an ongoing indolent specific immune reactivity driven by allopeptide specific CD4+ T cell clones (indirect pathway), which gives rise to cell-mediated and antibody responses directed against the mismatched MHC antigens of the graft; The specific aims of this proposal are to: 1. Determine the role of cell mediated and antibody-mediated immune responses in chronic rejection: We will determine if the pathologic finding of chronic rejection is associated with indirect alloreactivity and/or the development of de novo DSA; 2. Determine the gene expression profile associated with the development of chronic rejection: We will study intragraft expression patterns of key genes involved in the alloimmune, innate and antibody mediated responses at the time of transplantation and prospectively post-transplant to define the level of association between intragraft events and immune responses. We will determine if specific gene expression profiles predict the development of chronic rejection using microarray analysis; 3. Determine whether polymorphic variants of specific immunological genes confer susceptibility to chronic rejection: We plan to prospectively define transplant recipients genotypes for specific immunological genes in order to identify those genotypes associated with chronic rejection and the development of an immune response directed toward the graft. The results of these studies will lend greater insight to the underlying mechanisms leading to chronic rejection and help differentiate one cause of CAN.